[unreadable] Morphine is used for its therapeutic effects and abused for its euphoric effects. Use and abuse of this opiate can result in hippocampal deficits, which may impede treatment. New hippocampal neurons in the hippocampal subgranular zone (SGZ) are generated throughout adulthood and are suggested to play a role not only in hippocampal circuitry but also in hippocampal-dependent learning and memory. Evidence suggests that chronic morphine inhibits cell proliferation and adult neurogenesis in the rat SGZ, and this decrease may contribute to decreased hippocampal function in the addicted brain. The mechanism behind opiate-induced inhibition of adult neurogeneis is poorly understood. The aim of this proposal is to determine whether chronic morphine alters adult mouse hippocampal neurogenesis, and to examine how morphine impacts the cell cycle kinetics of mouse SGZ proliferating cells and other endogenous components that promote or maintain neurogenesis. Completion of these studies would enhance our understanding of morphine actions in the hippocampus, and would facilitate the use of transgenic mouse models to study the mechanisms underlying opiate-induced decrease in adult neurogenesis. Three specific aims are proposed. Aim 1: Demonstrate the utility of exogenous and endogenous cell cycle phase markers to analyze the approximate cell cycle phase and kinetics of the proliferating cells of the adult naive mouse SGZ. Aim 2: Evaluate the impact of chronic morphine on cell cycle phase and mature cell fate of the proliferating cells in adult mouse SGZ. Aim 3: Determine chronic morphine's action on factors that promote and maintain hippocampal neurogenesis. Immunohistochemistry, confocal microscopy, immunoblotting and in situ hybridizations are some of the techniques that will be utilized to study the above aims. Comprehension of the mechanisms underlying chronic morphine-mediated decrease in hippocampal neurogenesis will benefit addiction research, and may also shed light on general mechanisms of stem cell regulation. [unreadable] [unreadable] [unreadable] [unreadable]